Rheumatism is a refractory disease. Rheumatoid arthritis (RA), for example, has the basal lesion in proliferation of synovial cells accompanied with abnormalities in immune system caused by various factors. RA often causes progressive dysfunctions in articulation. To prevent from dysfunctions by RA, which is considered to be an autoimmune disease, agents correcting immune abnormalities are used in combination to general antiphiogistics under the expectation of altering natural couse of RA.
For remedy of arthritis, steroidal agents such as adrenocortical hormones including cortisone, non-steroidal anti-inflammatory agents such as aspirin, piroxicam and indometacin, antirheumatic agents such as gold preparations including aurothiomalate, D-penicillamines, and immunosuppressive agents such as cyclophosphamide and azathioprine have been used.
Recent Japanese reports suggest that an intermittent administration in low dose of methotrexate(MTX) result in high efficiency and rapid response. However, it has many side effects including interstitial pneumonia, stomatitis, gastrointestinal symptons such as nausea and vomition, fibrous liver, and marrow suppression. Furthermore, a long term of the therapeutic administrations may cause high infectiousness and complicated malignancy. There has been found no desirable drug which is really effective and has little side effects with respect to this disease.
Although many compounds having tubulin polymerization inhibitory activity have been reported, nothing but colchicine (an arthrifuge) and vincristine (an antineoplastic) (Cancer Research, vol.20,p1023,1960) among them are applicable for therapeutic agents. Rheumacon, the glycoside extracted from the natural material having antirheumatic effect is reported to show tubulin polymerization inhibitory effect (British Journal of rheumatology, Vol.32,p804,1993), but it has the unknown chemical structural formula and many side effects such as moon face, suffusion, and gastrointestinal disorder are reported.
The JP Laid-Open No.39256/1993 discloses that the other sulfonamides than those of the present invention are useful antineoplastics. N-[2-((4-hydroxyphenyl)amino)-3-pyridinyl]-4-methoxybenzenesulfonamide described in the publication is reported to show tubulin polymerization inhibitory effect (Cancer Research,Vol.54,p1702,1994).
However, the above agent has the severe side effects which make impossible its continuous administrations, the poor sustained therapeutic effects, or no effects for some patients. The clinical therapy demands low toxic agents which can protect and remedy patients from RA through new mechanism.